New immune-based strategies for cancer treatment including the activation of tumor-infiltrating CD8+ cytotoxic T lymphocytes (CTLs) have led to effective therapeutics against late-stage disease. However, the function of the immune system in combating the early-stage cancers remains uncertain. To establish a mechanism that activates immune cells against early carcinogenesis, we have studied the role of an epithelial-derived cytokine, thymic stromal lymphopoietin (TSLP), in early stages of breast cancer development. We have previously discovered that TSLP blocks breast carcinogenesis through the activation of CD4+ T cells that heavily infiltrate the sites of developing cancer in the breast gland without affecting the normal tissue.To investigate the mechanism by which TSLP-stimulated CD4+ T cells suppress spontaneous breast cancer development, we used MMTV-PyMT transgenic mouse models (PyMTtg) that spontaneously develop breast tumors and resemble the human luminal breast cancer. These mice were crossed into TSLP transgenic mice that produce TSLP under the promoter of a skin-specific keratin 14 promoter (K14-TSLPtg), plus additional knockouts including TSLPR-/- and IL4rα;-/-. Tumor development was arrested in K14-TSLPtg;PyMTtg mice compared to PyMTtg counterparts as their tumors failed to progress to high grade. The tumor suppressive mechanism of CD4+ T cells was mediated by a block in cancer cell proliferation, but not by cytotoxicity. Polarization of CD4+ T cells into T helper 2 (Th2) subtype was essential for blocking breast tumor development, and the tumor suppression was achieved by CD4+ T cells in the absence of CD8+ T and B cells. Finally, we found the basal levels of TSLP released by premalignant breast epithelial cells to be protective against the early phases of breast cancer development.In conclusion, we demonstrate that CD4+ Th2 cells block early stages of breast carcinogenesis. TSLP stimulated CD4+ Th2 cells induce an arrest in cancer cell proliferation, which represents a novel mode of immunity with great potential for the prevention and treatment of breast cancer.

Citation Format: Margherita Boieri, Anna Malishkevich, Lauren Steidl, Kenneth Ngo, Sowmya Iyer, Mary Awad, Johannes Kreuzer, Wilhelm Haas, Miguel Rivera, Shadmehr Demehri. T helper 2 cells block breast cancer promotion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4948.